This invention relates to a novel series of chemical compounds useful as HIV protease inhibitors and to the use of such compounds as antiviral agents.
Acquired Immune Deficiency Syndrome (AIDS) is a relatively newly recognized disease or condition. AIDS causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus III (HTLV-III), now more commonly referred to as the human immunodeficiency virus or HIV.
HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell's chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte cell which plays a vital role in the body's immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases such as, among others, pneumocystic carini pneumonia, Kaposi's sarcoma, and cancer of the lymph system.
Although the exact mechanism of the formation and working of the HIV virus is not understood, identification of the virus has led to some progress in controlling the disease. For example, the drug azidothymidine (AZT) has been found effective for inhibiting the reverse transcription of the retroviral genome of the HIV virus, thus giving a measure of control, though not a cure, for patients afflicted with AIDS. The search continues for drugs that can cure or at least provide an improved measure of control of the deadly HIV virus.
Retroviral replication routinely features post-translational processing of polyproteins. This processing is accomplished by virally encoded HIV protease enzyme. This yields mature polypeptides that will subsequently aid in the formation and function of infectious virus. If this molecular processing is stifled, then the normal production of HIV is terminated. Therefore, inhibitors of HIV protease may function as anti-HIV viral agents.
HIV protease is one of the translated products from the HIV structural protein pol gene. This retroviral protease specifically cleaves other structural polypeptides at discrete sites to release these newly activated structural proteins and enzymes, thereby rendering the virion replication-competent. As such, inhibition of the HIV protease by potent compounds may prevent proviral integration of infected T-lymphocytes during the early phase of the HIV-1 life cycle, as well as inhibit viral proteolytic processing during its late stage. Additionally, the protease inhibitors may have the advantages of being more readily available, longer lived in virus, and less toxic than currently available drugs, possibly due to their specificity for the retroviral protease.
In accordance with this invention, there is provided a novel class of chemical compounds that can inhibit and/or block the activity of the HIV protease, which halts the proliferation of HIV virus, pharmaceutical compositions containing these compounds, and the use of the compounds as inhibitors of the HIV protease.
The present invention relates to compounds falling within formula (9) below, and pharmaceutically acceptable salts, prodrugs, and solvates thereof, that inhibit the protease encoded by human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2). These compounds are useful in the treatment of infection by HIV and the treatment of the acquired immune deficiency syndrome (AIDS). The compounds, their pharmaceutically acceptable salts, and the pharmaceutical compositions of the present invention can be used alone or in combination with other antivirals, immunomodulators, antibiotics or vaccines. Compounds of the present invention can also be used as prodrugs. Methods of treating AIDS, methods of treating HIV infection and methods of inhibiting HIV protease are disclosed.
The compounds of the present invention are of the formula (9): ##STR1## wherein:
R and R' are independently selected from H, a substituted or unsubstituted alkyl-OR.sub.1 group, a cycloalkyl group substituted with a (C.sub.1 -C.sub.6)alkyl group or a (C.sub.1 -C.sub.6)alkyl-OH group, a heterocycle group substituted with a (C.sub.1 -C.sub.6)alkyl group or a (C.sub.1 -C.sub.6)alkyl-OH group, an alkyl-NR.sub.2 R.sub.3 group, or an alkyl-S(X) (Y)R.sub.4 group,
wherein
R.sub.1 is H, a substituted or unsubstituted alkyl group, or an acyl group; PA1 R.sub.2 and R.sub.3 are each independently selected from H, substituted or unsubstituted alkyl, cycloalkyl, heterocycle, and aryl groups, and acyl and sulfonyl groups; PA1 R.sub.4 is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocycle, or aryl group; and PA1 X and Y are each independently selected from =O and nothing;
or a pharmaceutically acceptable prodrug, salt or solvate thereof.
Preferably in the compounds of formula 9, R is H. More preferably, R is H and R' is a cycloalkyl group selected from: ##STR2## Preferably in the compounds of formula 9 when at least one of R and R' is an alkyl-OR.sub.1 group, R.sub.1 is H. Particularly when at least one of R and R' is an alkyl-OR.sub.1 group, the alkyl-OR.sub.1 is selected from --C(CH.sub.3).sub.2 CH.sub.2 OH, --CH(CH.sub.3)CH.sub.2 OH, --CH.sub.2 CH.sub.2 OH, --C(CH.sub.3) (CH.sub.2 OH).sub.2, --C(CH.sub.3).sub.2 --O--CH.sub.2 --O--CH.sub.3, --C(CH.sub.3).sub.2 CH.sub.2 --O--CH.sub.2 --O--CH.sub.3, and --C(CH.sub.3).sub.2 CH.sub.2 --O-- acyl, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
Preferably when at least one of R and R' is a cycloalkyl group substituted with a (C.sub.1 -C.sub.6)alkyl group or a (C.sub.1 -C.sub.6)alkyl--OH group, the cycloalkyl group is selected from: ##STR3## Preferably when at least one of R and R' is a heterocycle group substituted with a (C.sub.1 -C.sub.6)alkyl group or a (C.sub.1 -C.sub.6)alkyl--OH group, the heterocycle group is selected from: ##STR4## wherein R.sub.3 is H, a substituted or unsubstituted alkyl, cycloalkyl, heterocycle, or aryl group, or an acyl or sulfonyl group.
A preferred species of the formula (9) is [3S-[2(2S*,3S*),3 alpha,4a beta,8a beta]]-N-(1,1-dimethyl-2-hydroxyethyl)decahydro-2-[2-hydroxy-3-[(3 -hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-3-isoquinolinecarboxam ide ##STR5## and its pharmaceutically acceptable salts, and its prodrug analogs. Preferred prodrugs can be obtained by replacing the hydrogen in one of the alcohol groups with an acyl group, and more preferably an amino acid acyl group.
The present invention further provides pharmaceutical formulations comprising an effective amount of a compound of formula (9) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, such as a diluent or excipient.
The present invention further provides a method of treating AIDS comprising administering to a host or patient, such as a primate, an effective amount of a compound of the present invention.
The present invention further provides a method of inhibiting HIV replication comprising administering to an HIV infected cell, a cell susceptible to HIV infection or a host or patient, such as a primate, an effective amount of a compound of the present invention.